EP2136653B1 - Embedded liquid lubricants for tableting - Google Patents

Embedded liquid lubricants for tableting Download PDF

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Publication number
EP2136653B1
EP2136653B1 EP08745723.0A EP08745723A EP2136653B1 EP 2136653 B1 EP2136653 B1 EP 2136653B1 EP 08745723 A EP08745723 A EP 08745723A EP 2136653 B1 EP2136653 B1 EP 2136653B1
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EP
European Patent Office
Prior art keywords
composition
matrix
multivitamin
vitamin
lubricant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP08745723.0A
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German (de)
English (en)
French (fr)
Other versions
EP2136653A1 (en
Inventor
Yong Dai
Alan M. Goldberg
Michael A. Goode
Raymond Alan Bartolucci
James O. Frazier
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Wyeth LLC
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Wyeth LLC
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Filing date
Publication date
Application filed by Wyeth LLC filed Critical Wyeth LLC
Priority to DK13154734.1T priority Critical patent/DK2599394T3/en
Priority to PL08745723T priority patent/PL2136653T3/pl
Priority to EP13154734.1A priority patent/EP2599394B1/en
Priority to PL13154734T priority patent/PL2599394T3/pl
Publication of EP2136653A1 publication Critical patent/EP2136653A1/en
Application granted granted Critical
Publication of EP2136653B1 publication Critical patent/EP2136653B1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/10—Securing foodstuffs on a non-edible supporting member
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/20—Agglomerating; Granulating; Tabletting
    • A23P10/25—Agglomeration or granulation by extrusion or by pressing, e.g. through small holes, through sieves or between surfaces
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/20—Agglomerating; Granulating; Tabletting
    • A23P10/28—Tabletting; Making food bars by compression of a dry powdered mixture
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • This invention relates to pharmaceutical and nutriceutical tablets. More particularly the invention provides a composition for effective lubrication in tableting.
  • Stearic acid or metallic salts of stearic acid are commonly used as an excipient in pharmaceutical and nutriceutical compositions to facilitate the tableting process.
  • Compounds such as magnesium stearate function as a lubricant and facilitate tableting by reducing friction at the tablet-die wall interface during tablet formation and ejection, and/or by preventing sticking to punch faces and the die wall.
  • Magnesium stearate is a laminar lubricant.
  • As a laminar lubricant the structure of magnesium stearate is a stack of laminar sheets. Lubrication occurs when one or more laminar sheets are "peeled off' the stack and at least partially coat surrounding particles. Mixing facilitates removal of sheets from the stack and accordingly the degree of lubrication (i.e. lubrication with a laminar lubricant is "mixing sensitive").
  • the laminar sheets peel off from the stack structure of magnesium stearate and coat the surrounding particles or granules of the composition. Accordingly, the mixing time, speed and/or mixing method impact the lubricating efficacy of magnesium stearate. For example, if too many laminar sheets peel off from the stack structure of magnesium stearate in the mixing process over lubrication occurs. Namely, particles get over coated with laminar sheets which reduce interparticular bonding leading to poor compressibility and lower tablet hardness, thus creating potential processing problems and/or the propensity for malformed tablet. In some cases over lubrication can render the tablet hydrophobic which may lengthen disintegration time undesirably.
  • magnesium stearate is typically added to the composition in a separate last step before tableting to provide control of the lubrication process and minimize the opportunity for over-lubrication or undesirable disruption of the magnesium stearate structure in the mixing process.
  • liquid lubricants have not been particularly useful in powder blend compositions of nutriceuticals and/or pharmaceuticals intended for tableting.
  • liquid lubricants can only be added in small quantities to powder blends and must be added immediately prior to compression because they tend to wet the powder blends rendering mixing difficult.
  • a second approach used to facilitate use of liquid lubricants in dry mixtures intended for tableting was to coat liquid lubricants with an oil-insoluble film-forming substance to avoid the wetting issue.
  • the film forming material assembles to form a layer or skin over the surface of an oil droplet.
  • Film forming substances as set forth in U.S. Patent 3,518,343 include water soluble gums such as gum Arabic, pectin, traganth, modified celluloses such as hydroxypropyl cellulose or carboxymethyl cellulose, alginates or proteinaceous material such as gelatin.
  • WO 91/04018 discloses a dry particulate tableting aid comprising a particulate magnesium carbonate having a liquid lubricant oil adsorbed thereon, wherein the weight ratio of oil to magnesium carbonate is between 0.15:1 and 0.6:1.
  • compositions and/or method for improved lubrication of dry nutriceutical and/or pharmaceutical compositions for tableting is needed.
  • the invention provides a multivitamin and mineral composition for tableting comprising 0.1% to 1.5% wt/wt of a matrix with embedded lubrication, wherein the matrix with embedded lubrication comprises 50% by weight of an oily liquid finely dispersed in an oil insoluble material, and wherein the composition is substantially free of stearate.
  • the oily liquid dispersed in the oil insoluble material is selected from the group consisting of Vitamin E, preferably in the form of Vitamin E acetate, animal oil, synthetic oil, mineral oil, polyethylene glycol, silicon oil and combinations thereof.
  • Suitable oil insoluble materials include, but are not limited to, starch, dextrin, microcrystalline cellulose, ethylcellulose, gelatin, sugars, glucose, maltose, fructose, sorbitol, sucrose, mannitol, sorbitol, lactose, methylcellulose, hydroxypropylmethyl cellulose, maltodextrin, silicon dioxide, anhydrous dicalcium phosphate, and combinations thereof.
  • the composition may be a direct compression, roller compaction or granulation composition.
  • a method of lubricating a nutritional supplement or pharmaceutical composition for tableting comprises providing a matrix with embedded liquid lubricant, providing a nutritional supplement composition or pharmaceutical composition, mixing the matrix with embedded liquid lubricant and the nutritional supplement or pharmaceutical composition, and forming a tablet.
  • the nutritional supplement or pharmaceutical composition may be a direct compression mixture, a roller compaction mixture or comprise a granulation.
  • the present invention provides a composition comprising a matrix with one or more embedded liquid lubricants.
  • the embedded liquid lubricants serve to provide lubrication for tableting of the composition.
  • the matrix with embedded liquid lubricant of the invention is an oil-insoluble-particulate-solid base material having a viscous oily liquid lubricant dispersed in the base material.
  • the matrix with embedded liquid lubricant may be used as an alternative to metal stearate lubricants such as magnesium stearate as a tableting lubricant for nutriceutical or pharmaceutical compositions.
  • the matrix with embedded lubricant may be used as a partial replacement for stearate lubricants or other tableting lubricants.
  • the matrix with embedded lubricant is a useful lubricant for tableting dry nutritional and/or pharmaceutical compositions such as, for example, vitamin and/or mineral compositions.
  • the matrix with embedded lubricant is particularly useful for compositions subjected to direct compression in the tableting process.
  • liquid Vitamin E acetate finely dispersed in a starch/dextrin matrix was found to effectively lubricate a multi-vitamin and mineral formulation for direct compression.
  • Embodiments having Vitamin E as the lubricant embedded in the matrix may provide the additional benefits of antioxidant activity and/or nutritional supplementation of Vitamin E.
  • a method of lubricating a nutritional or pharmaceutical composition for tableting by providing a matrix with embedded liquid lubricant, and a nutritional supplement or pharmaceutical composition, and mixing the matrix with embedded liquid lubricant with the nutritional supplement or pharmaceutical composition prior to tableting.
  • the inventors believe without wishing to be bound to the theory that embedding a liquid lubricant in a matrix allows the liquid lubricant to be evenly distributed in the matrix without wetting the matrix.
  • the liquid lubricant may be extruded from the matrix and provide lubrication for tableting, eliminating the over-lubrication issues seen with stearic acid and metal stearates. Since the liquid lubricant in a matrix does not have mixing related over-lubrication issues, it can be added with other components for mixing in a single step. Thus, the conventional step of adding lubricant as a separate step immediately before tableting can be avoided.
  • matrix with embedded liquid lubricants means a composition comprising at least one oily liquid finely dispersed in an oil insoluble material wherein the matrix appears to be dry and no oil or oily appearance is visible to the human eye and the matrix is free flowing. Small particles of oil are incorporated in the mass of the oil insoluble material (e.g. interspersed in the interstitial spaces of the oil insoluble material.) The lubricant may be displaced from the matrix by the compression forces of the tableting process.
  • the oil insoluble material may be a single component or mixture of components. Typically, the oil insoluble material is in the form of dry particles.
  • the oily liquid may be a single entity or a mixture of oily liquids.
  • Each of the materials comprising the matrix with embedded liquid lubricants should be a material that is acceptable for consumption by a mammal.
  • oil means a substance that is substantially insoluble in water (as designated by the Merck Index, CRC Handbook or MSDS Data sheet) and that is a liquid at ambient temperatures.
  • An "embedded liquid lubricant” includes oils as well as other materials which are liquids at ambient temperatures, have lubricating properties, and do not react with or solubilize the oil insoluble material.
  • Embedded liquid lubricants are distinguished from film-coated lubricants in that there is no chemical or physical process that causes the oil insoluble material to assemble a layer over the surface of an oil droplet.
  • a simple listing of oil insoluble materials suitable for forming a matrix and a listing of film forming polymers may over lap; however, chemical identity alone is not dispositive.
  • the method of combining, proportions used, the presence of other reactive entities, amount of moisture and temperature are exemplary of factors that may determine whether a film-coated oil is formed or a matrix with embedded lubricant is formed.
  • stearate(s) includes stearic acid and metallic salts of stearic acids.
  • Magnesium stearate is an exemplary metallic salt of stearic acid.
  • Substantially, free of stearates means that the composition comprises less than 0.01% stearate by weight.
  • multivitamin and mineral or “multivitamin and multimineral” supplement(s) includes compositions comprising, at least one vitamin and at least one mineral and optionally one or more related nutritional agent.
  • multivitamin and mineral or “multivitamin and multimineral” should be interpreted in a like manner herein when they proceed the terms “ supplement”, “tablet”, or “composition”. Additionally multivitamin and mineral supplement is an example of nutritional supplement and/or a nutriceutical.
  • Nutritional agents include substances other than vitamins and minerals known to have health benefits.
  • Nutritional agents include, but are not limited to, carotinoids (such as lutein, lycopene, zeaxanthin, astaxantin, and related xanthanins), fiber, phytosterols, glucosides, polyphenols, B complex related compounds (such as choline and inositol), omega-3 fatty acids, probiotics, glucosamine, herbals, amino acids and peptides.
  • disintegration time means the amount of time it takes for a tablet dosage unit of a pharmaceutical composition or nutritional supplement to disintegrate under controlled laboratory conditions.
  • disintegration time means the amount of time it takes for a tablet dosage unit of a pharmaceutical composition or nutritional supplement to disintegrate under controlled laboratory conditions.
  • One of ordinary skill in the art is familiar with methods and procedures for determination of disintegration times.
  • dry pharmaceutical composition refers to a composition that is presented as a dry material for compressing into a tablet dosage form. While the composition is dry at the time of compression into a tablet, processing steps that involve moisture are not precluded so long as the material is not overtly moist at the time it is presented for tableting.
  • pharmaceutical active(s) As used herein the terms “pharmaceutical active(s)”, “active(s)”, “active agent(s)”, “therapeutic agent(s)”, drug(s)” should be considered to be equivalent terms and taken to mean a substance used in the prevention, diagnosis, alleviation, treatment, or cure of disease or medical condition.
  • composition of the invention may comprise any nutritional or pharmaceutical composition, which may be formed into a tablet dosage form.
  • Compositions with a plurality of nutritional components and/or pharmaceutical actives are also within the scope of the invention.
  • the composition may comprise a single nutritional component, a select group of components (such as, for example, a group of nutrients directed to bone health), or a wide spectrum of nutritional components such as vitamins and minerals, and optionally, one or more nutritional agents (such as, for example, commercial multivitamin and mineral tablets or multivitamin and mineral tablets with one or more added nutritional agents.)
  • Suitable vitamins and related entities which may be included in the compositions of the invention include, but are not limited to, Vitamin C, Vitamin E, thiamin (Vitamin B 1 ), riboflavin (Vitamin B 2 ), niacin (Vitamin B 3 ), pyridoxine (Vitamin B 6 ), folic acid, cobalamins (Vitamin B 12 ), Pantothenic acid (Vitamin B 5 ), Biotin, Vitamin A (and Vitamin A precursors), Vitamin D, Vitamin K, and other B complex vitamins, and mixtures thereof.
  • Suitable minerals which may be included in the composition of the invention include, but are not limited to, iron, iodine, magnesium, zinc, selenium, copper, calcium, manganese, silicon, molybdenum, vanadium, boron, nickel, tin phosphorus, chromium, cobalt, chloride, potassium and combinations thereof.
  • Mineral components of multivitamin-multimineral tablets are typically provided in salt form.
  • the salt form used should be a pharmaceutically acceptable salt form.
  • a listing of vitamins and minerals and related agents that may be included in nutritional supplements and dosage amounts are set forth in established reference guides such as the United States Pharmacopeia National Formulary Official Compendium of Standards (i.e., the U.S.P. N.F. Official Compendium of Standards) or European Directive 90/496/EC including amendments which are incorporated herein by reference.
  • Amounts of vitamins and minerals may vary in specific embodiments but should typically fall within the dosage amounts set forth in the U.S.P. N.F. Official Compendium of Standards or European Union Directive
  • Nutritional agents which may be included in the composition of the invention include, but are not limited to, carotinoids (such as lutein, lycopene, zeaxanthin, astaxanthin, and related xanthins), B complex related compounds such as choline and inositol, for example, fiber, phytosterols, probiotics, glucosides, polyphenols, choline, omega-3 fatty acids, glucosamine, herbals, amino acids and peptides.
  • carotinoids such as lutein, lycopene, zeaxanthin, astaxanthin, and related xanthins
  • B complex related compounds such as choline and inositol, for example, fiber, phytosterols, probiotics, glucosides, polyphenols, choline, omega-3 fatty acids, glucosamine, herbals, amino acids and peptides.
  • compositions of the invention further comprise a matrix with embedded liquid lubricant.
  • the matrix comprises a base material portion and an oily liquid.
  • the base material portion is an oil insoluble material.
  • Oil insoluble materials suitable for the base material portion include, but are not limited to, starch, dextrin, microcrystalline cellulose, ethylcelluloseose, gelatin, sugars, glucose, maltose, fructose, sorbitol, sucrose, mannitol, sorbitol, lactose, methylcellulose, hydroxypropylmethyl cellulose, maltodextrin, silicon dioxide, anhydrous dicalcium phosphate, and combinations thereof.
  • the oily liquid is selected from the group consisting of Vitamin E (preferably in the form of Vitamin E acetate), animal oil, synthetic oil, mineral oil, polyethylene glycol, silicon oil and combinations thereof.
  • a processing aid such as, for example, silicon dioxide.
  • the base material should be in a substantially particulate state in the matrix such that interparticulate spaces (or interstitial spaces) are available for receiving the small particles or fine droplets of the lubricant.
  • the oily liquid is finely dispersed in the base material. Dispersion of the oily liquid in the base material should be such that the matrix appears to be dry and no oil or oily appearance is visible to the human eye and the matrix is free flowing.
  • the amount of oily liquid dispersed in the matrix is 50% by weight. This amount is convenient for maintaining the properties of the matrix and providing optimized quantities of lubricant per amount of matrix used in the tableting composition.
  • Vitamin E acetate from a starch maltodextrin base material under compression differs from the release of Vitamin E acetate from a starch gelatin base material under compression.
  • Adding processing aids such as silicon dioxide, for example, is exemplary of methods that may be used to modulate the flow properties.
  • the matrix is to be used in a composition intended for direct compression, preferably at least 70% of the matrix will have particle sizes that fall in the range of about 20 mesh (850 microns) to about 200 mesh (75 microns) as measured by US standard sieves. Additionally, for direct compression, the matrix with embedded lubricant will preferably have a Carr compressibility Index value of about 5 to about 21.
  • Amounts of matrix used depend on amount of lubrication needed which, in turn, is a function of the chemical and physical properties of activities and excipients in the composition.
  • amounts of lubricant as low as about 0.1% to about 1.5% wt/wt of a matrix which is 50% by weight of lubricant may provide sufficient lubrication.
  • the dispersion of the oily liquid in the base material may be accomplished with mixing.
  • Base material particle size, speed of mixing and mechanism of mixing are exemplary of parameters which may be modified to achieve the desired dispersion.
  • small base material particle size and high shear mixing may be used to create the fine dispersion in which the oil is not visible to the human eye.
  • Other methods such as spray processes, for example may be likewise suitable to finely disperse the oily liquid in the base material.
  • the base material comprises one or more materials that may react or assemble to form films under certain conditions, the method selected for preparing the matrix with embedded lubricant should avoid processing steps and or addition of substances that would lead to film formation.
  • Vitamin E may have some advantages over other traditional lubricating oils. Most traditional lubricating oils contain trans fats, which are associated with an increased risk of coronary heart disease. On the contrary, Vitamin E has been suggested to also assist in healthy heart and blood vessels. Furthermore, Vitamin E is widely acknowledged as a powerful antioxidant. Vitamin E is used as a supplement to prevent the destructive impacts of free radicals in human. Also Vitamin E is widely used as a preservative in a variety of consumer goods to maintain quality and/or prevent undesirable reactions and extend shelf life. Vitamin E may be used in free form or in a derivatized form such as, for example, Vitamin E acetate. form or in a form such as, for example, Vitamin E acetate.
  • a matrix with embedded Vitamin E is widely applicable as a tableting lubricant.
  • a matrix with embedded vitamin E can effectively lubricate a direct compression multi-vitamin/mineral formulation, which contains high levels of abrasive metal salts. Abrasive materials such as metal salts are believed to make lubrication difficult.
  • the matrix with embedded Vitamin E can be an effective sole lubricant for the multi-vitamin/mineral formulation, or the matrix with embedded vitamin E may be employed in conjunction with another lubricant for various tabletable formulations.
  • a matrix with vitamin E embedded is also suitable for use in compression blends with less abrasive materials, compositions subjected to roller compaction or in granulation compositions subjected to tableting.
  • compositions in accordance with the present invention are intended for tableting to make a solid form (i.e. tablet) for oral administration.
  • the composition may further comprise excipients and/or processing aides in addition to vitamins and minerals.
  • excipients and processing aids include but are not limited to, absorbents, diluents, flavorants, colorants, stabilizers, fillers, binders, disintegrants, glidants, antiadherents, sugar or film coating agents, preservatives, buffers, artificial sweeteners, natural sweeteners, dispersants, thickeners, solubilizing agents and the like or some combination thereof.
  • stearic acid and/or metal stearate lubricants are not included as excipients.
  • the nutritional compositions of the invention may be prepared by combining the matrix with embedded lubricant with the vitamin(s) and/or mineral(s) and/or nutritional agent(s) intended for inclusion in the tablet dosage form and tableting excipients.
  • the matrix with embedded lubricant is not mixing sensitive, the timing and /or manner of a addition of the matrix with embedded lubricant is not critical. Accordingly, a special addition step or steps for addition of the lubricant and /or special mixing provisions for the lubricant are not required.
  • the composition thus prepared may be fed into a tablet press and formed into tablets.
  • the compression forces of the tablet press are sufficient to extrude lubricant from the matrix to permit lubrication.
  • the matrix with embedded lubricant is well suited for use with direct compression blends (e.g. compositions prepared for direct compression).
  • a matrix with embedded lubricants may likewise be useful for lubrication of granulation blends intended for tableting or compositions prepared by roller compaction as the lubrication function is achieved as the composition is pressed into a tablet.
  • compositions of pharmaceutical actives for tableting utilizing a matrix with embedded lubricant as a tableting lubricant may be prepared as described above for the nutritional compositions.
  • a matrix with embedded lubricant is Vitamin E acetate dispersed in a base material of equal parts of modified food starch and maltodextrin.
  • the ratio of vitamin E to base material is about 50/50 by weight.
  • Silicon dioxide may be included in the matrix as a processing aid. Typically the processing silicon dioxide processing aid would be included in an amount of about 0.2 to 2.5%.
  • the vitamin E, starch, maltodextrin and processing aid should be mixed such that the oily viscous vitamin E is finely dispersed in the starch maltodextrin base material and no liquid or viscous material is visible to the human eye. Mixing may be accomplished using a high shear mixer or alternatively a spray system.
  • the mixing method should yield a matrix in the form of a free flowing powder. Once prepared, the matrix with embedded lubricant may then be combined with the material to be tableted.
  • This composition is representative of the many matrix compositions that are within the scope of the invention and is provided for illustrative purposes.
  • Table 1 An example of a nutritional supplement composition of an exemplary embodiment of the invention is provided in Table 1. This composition is representative of the many compositions that are within the scope of the invention and is provided for illustrative purposes.
  • the exemplary composition of Table 1 is a multivitamin and mineral supplement.
  • the matrix with embedded lubricant is vitamin E finely dispersed in a starch maltodextrin base (50% w/w) with silicon dioxide as a processing aid as described in Example 1.
  • the amount of matrix with embedded lubricant was varied from 0.3% to 8.8% for the individual samples of the nutritional supplement composition and accordingly is listed as a range of amounts in Table 1.
  • the matrix with embedded lubricant was the sole lubricant in the composition (e.g.
  • the tablets were 0.330 inch wide, 0.745 inch long and approximately 0.280 inch thick (with slight variation in size do to the varying amounts of matrix with embedded lubricant used).
  • the Manesty Betapress was instrumented to monitor both compression force and ejection force, and recorded results using MCC software. Tablets were evaluated for hardness by Hardness Tester (Dr. Schleuniger Pharmatron, Model 6D-500N), friability by Vanderkamp Friabilator (Van-Kel Industry, Model 10809), weight by Analytical Balance and thickness by Caliper.
  • the Vitamin E matrix performed well as the sole lubricant with minimal impact on tablet hardness, friability, and disintegration time (DT).
  • the compression mixtures were found to be well lubricated for compression and subsequent ejection from the dies with a minimum of 0.3% matrix with embedded Vitamin E by weight (or 0.15% Vitamin E), and smooth surfaced and elegant in appearance with a minimum of 1.2% Matrix with embedded Vitamin E (or 0.6% Vitamin E). 0.3% of matrix with embedded Vitamin E was sufficient for providing equivalent ejection forces as a comparable vitamin and mineral supplement in which 0.3% Magnesium stearate is used as the lubricant.
  • the matrix with embedded Vitamin E was found to decrease the friability by approximately 50% at all concentrations tested (0.3 - 8.8%) as compared to a comparable tablet composition differing only in the use of magnesium stearate as a tableting lubricant.
  • the presence of matrix with embedded Vitamin E at low concentrations (0 -1.2%) did not show significant impact on disintegration times, however, increased the disintegration times from 0.9 to 2 and 4 min at higher concentrations (2.4% and 4.6%). It is well know in the art that for vitamin and mineral compositions addition magnesium stearate even at low concentrations (ca. 0.3%) usually increases disintegration times due to the hydrophobic nature it imparts on the compression blend.
  • the matrix with embedded Vitamin E was also found to be compatible with other ingredients in vitamin and mineral tablets.
  • the Vitamin E was fully recoverable and stable after compressed into tablets based on an accelerated stability study. No significant impacts of the Matrix with embedded Vitamin E were observed on the stability of other ingredients in vitamin and mineral tablets.
  • a vitamin and mineral composition with 0.3% Magnesium stearate in place of the matrix with embedded Vitamin E but alike in all other respects was also prepared and compressed after mixed in the Littleford for 0, 2, 4, 10, and 20 minutes.
  • Increasing the mixing time significantly reduced tablet hardness, slightly decreased ejection force, and significantly increased friability for tablets of using 0.3% magnesium stearate as a lubricant.
  • Table 2 shows exemplary data for tablet hardness for tablets compressed at 40kN after 0, 2, 4, 10 and 20 minutes of mixing.

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EP08745723.0A 2007-04-16 2008-04-14 Embedded liquid lubricants for tableting Active EP2136653B1 (en)

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DK13154734.1T DK2599394T3 (en) 2007-04-16 2008-04-14 Embedded liquid lubricants for tableting
PL08745723T PL2136653T3 (pl) 2007-04-16 2008-04-14 Osadzone ciekłe środki smarujące do tabletkowania
EP13154734.1A EP2599394B1 (en) 2007-04-16 2008-04-14 Embedded liquid lubricants for tableting
PL13154734T PL2599394T3 (pl) 2007-04-16 2008-04-14 Osadzone ciekłe środki smarujące do tabletkowania

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US11/787,381 US20080254119A1 (en) 2007-04-16 2007-04-16 Imbedded liquid lubricants for tableting
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BR112022002135A2 (pt) 2019-08-08 2022-04-19 Evonik Operations Gmbh Método de preparação de uma forma de dosagem sólida e um lubrificante
KR20220114618A (ko) * 2019-12-17 2022-08-17 9286-3620 퀘벡 인크. 단백질/폴리사카라이드 코아세르베이트의 인시츄 형성에 기반한 경구 전달 시스템

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US20140342047A1 (en) 2014-11-20
HUE035179T2 (hu) 2018-05-02
DK2136653T3 (en) 2018-01-22
CA2682551C (en) 2017-03-28
KR20100016514A (ko) 2010-02-12
CO6220919A2 (es) 2010-11-19
JP5615170B2 (ja) 2014-10-29
IL201495A (en) 2017-03-30
DK2599394T3 (en) 2018-08-13
RU2012138912A (ru) 2014-03-20
TW200906317A (en) 2009-02-16
KR101867139B1 (ko) 2018-06-12
CA2682551A1 (en) 2008-10-30
JP2010524951A (ja) 2010-07-22
US20170251711A1 (en) 2017-09-07
EP2599394A1 (en) 2013-06-05
AU2008242256B2 (en) 2011-11-03
NO2136653T3 (zh) 2018-04-28
RU2615823C9 (ru) 2017-07-12
MX340643B (es) 2016-07-19
CN105360879B (zh) 2020-12-04
PL2136653T3 (pl) 2018-03-30
JP2014195459A (ja) 2014-10-16
EP2599394B1 (en) 2018-06-13
PT2599394T (pt) 2018-07-13
PH12009501979A1 (en) 2008-10-30
CN101657109A (zh) 2010-02-24
ZA200907217B (en) 2010-11-24
ECSP099676A (es) 2009-11-30
IL201495A0 (en) 2010-05-31
WO2008130883A1 (en) 2008-10-30
HK1216227A1 (zh) 2016-10-28
KR20150068490A (ko) 2015-06-19
US11013251B2 (en) 2021-05-25
EP2136653A1 (en) 2009-12-30
MY146906A (en) 2012-10-15
US20080254119A1 (en) 2008-10-16
RU2473243C2 (ru) 2013-01-27
HUE038703T2 (hu) 2018-11-28
RU2615823C2 (ru) 2017-04-11
PT2136653T (pt) 2018-01-15
CN105360879A (zh) 2016-03-02
TWI433652B (zh) 2014-04-11
RU2009136554A (ru) 2011-05-27
ES2655552T3 (es) 2018-02-20
NZ580136A (en) 2012-02-24
MX2009011058A (es) 2009-10-29
BRPI0810017A2 (pt) 2014-09-16
AU2008242256A1 (en) 2008-10-30
PL2599394T3 (pl) 2018-10-31

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